Processes for the preparation of 5beta-h-6-keto steroids

ABSTRACT

THIS INVENTON IS DIRECTED TO PROCESSES FOR THE SYNTHESIS OF 2,3-SUBSTITUTED-5B-H-6-KETO-STEROIDS WHICH ARE USEFUL AS METAMORPHOSIS HORMONES AND ARE ADDITIONALLY USEFUL AS INTERMEDIATES FOR THE PRODCUCTION OF OTHER INSECT HORMONES.

United States Patent PROCESSES FOR THE PREPARATION OF 5fi-H-6-KETOSTEROIDS Andor Fiirst and Andr Furl'en'meiter, Basel, Albert Langemann,Binningen, and Guy Waldvogel, Riehen, Switzerland, and Peter Hooks,Ulrich Kerb, and Rudolf -Wi e'chert, Berlin, Germany, assignors toHolfmanniLa Roche Inc., Nutley, NJ. No=Drawing. 0riginal applicationFeb. 29, 1968, Ser. No. 709,238. Divided and this application June 1,1970, Ser.No.; 42,5 95 7 Claims priority. application Switzerland, Aug.13, 1965, 11,430/65; Def. '8, 19.65,'13,907/65; Jan. 28, 1966, l1,2 31/66;'Mar. 24, 1966, 4,336/66; Germany, Sept. 24, 1965; Sch 37,774;'0ct;"15, 1965, Sch 37,892; Jan. 27, 1966, Sch 38,384; Jan; 29, '1966,Sch 38,399

Int.Cl. C07c 167/16, 173/00 Us. (:1. 260-23955 5 Claims i V ABSTRACT orTHE DISCLOSURE This invention is directed to processes for the synthesisof 2,3 substituted=5B-H-6-keto-steroids which are useful asmetamorphosis hormones and are additionally useful as intermediates forthe production of other insect hormones.

c c I RELATED APPLICATIONS This application is a divisionof-applicantscopending application Ser. No. 709,238, filed Feb. 29, 1968, which inturn is a divisional application of application Ser. No. 571,187, filedAug. 9, 1966, now abandoned.

- :DETAILED DESCRIPTION OF THE INVENTION wherein R is hydrogen ormethyl; R is hydrogen, hydroxy, loweracyloxy, or lower alkoxy; R ishydroxy, lower acyloxy, or lower 'alkoxy; R and R when taken togetherand-when R? is in: the fl-orientation, are lower alkylenedioxyi A-represents-a single or a double bond; R is hydrogen or hydroxy; R ishydrogen or lower alkyl; R", whenR is lower alkyl, is hydroxy or loweracyloxy', and when'R is hydrogen, is hydroxy, lower acyloxy, or aradical of theformula -C(OH )R R R when taken alone, is hydrogenorhydroxy; R when taken alone, is

tcnagcqz, aliphatic hydrocarbyl or aliphatic hydrocarbyl substitutedwith up to 2-substituents of the group consistingaof.:hydroxy, loweracyloxy, lower alkoxy, or

tetrahydropyranyloxy; R and R when taken together, are 0x0; and Z ishydrogen or lower alkyl.

By the term lower acyloxy is meant a radical derived from an aliphaticcarboxylic acid of up to about 11 carbons by removal of the hydrogen ofthe carboxyl group. The acid may be saturated or unsaturated, straightor branched chain, and may contain one or more substituents, such ashalo, including chloro and fluoro, nitro, oxy, and the like. Suitableacids include formic acid, acetic acid, propionic acid, trimethylaceticacid, caproic acid, enanthic acid, hendecanoic acid, phenylacetic acid,benzoic acid, cyclopentylpropionic acid, trifiuoroacetic acid,aminoacetic acid, oxypropionic acid, adipic acid, and the like.Preferred are hydrocarbyl acyclic mono-basic acids of up to about 6carbons, with alkanoic mono-carboxylic acids being especially preferred.

By the terms lower alkyl and lower alkoxy are meant alkyl and alkoxygroups of up to about 6 carbons, such as methyl, ethyl, propyl,isopropyl, butyl, tert.-butyl, hexyl, methoxy, ethoxy, tert.-butoxy, andthe like.

By the term lower alkylenedioxy group is meant a divalent radical of theformula OR O-, wherein R is an alkylene, i.e., a divalent saturatedacyclic hydrocarbon, radical of up to about 10 carbons, and preferablyup to about 6 carbons. Especially preferred are alkylidenedioxy groups,with isopropylidenedioxy being most preferred.

By the term aliphatic hydrocarbyl group is meant a monovalent radicalfree of aromatic unsaturation and consisting of carbon and hydrogen,such as alkyl, alkenyl, alkynyl, alkadienyl, and the ilke, and may beeither branched or straight chain. Preferred aliphatic hydrocarbylgroups are alkyl groups and alkynyl groups of up to about 6 carbons,such as ethynyl, propyl, isopropyl, butyl, isobutyl, butynyl, pentyl,isopentynyl, and the like, with branched-chain groups being preferred.Preferred substituted aliphatic hydrocarbyl groups are those representedby the formula CH(OH)R wherein R is aliphatic hydrocarbyl of up to about5 carbons, preferably branched chain, and especially branched alkyl oralkynyl which may be substituted with a hydroxyl group, a lower alkylgroup, a lower alkoxy group, or a tetrahydropyranyl group.

The novel products of this invention are illustrated by the followingformulae:

wherein:

R and R are as defined above;

R and R each when taken alone, is hydroxy, lower acyloxy, or loweralkoxy, and R and R can be the same or different;

R and R when taken together, and R is in the orientation, are loweralkylenedioxy;

A is as defined above;

R is hydrogen or lower alkyl;

R, when R is lower alkyl, is hydroxy or lower acyloxy, and when R ishydrogen, is hydrogen, lower acyloxy, or a radical of the formula C(CH)R R R when taken alone, is hydrogen or hydroxy;

R when taken alone, is -CO Z, CHO,

CH-60-lower alkyl) {CH CO Z, aliphatic hydrocarbyl, or aliphatichydrocarbyl substituted with up to two substituents of the groupconsisting of hydroxy, lower acyloxy, lower alkoxy, ortetrahydropyranyloxy;

R when taken alone, and when R is hydrogen, is CO Z, -CHO, CHtO-loweralkyl) {CH -hCO Z, or aliphatic hydrocarbyl, and when R is hydroxy, is RR and R when taken together, are oxo;

R and R", when taken together, are oxo;

Z is hydrogen or lower alkyl;

R, when A represents a single bond, is hydrogen, and

when A represents a double bond, is hydrogen or hydroxy;

Y is hydrogen, lower alkyl, or lower acyl; and

R is aliphatic hydrocarbyl or aliphatic hydrocarbyl substituted with upto one substituent of the group consisting of hydroxy, lower acyloxy,lower alkoxy, or tetrahydropyranyloxy.

An especially preferred class of compounds of this invention are thosedefined by the formula:

COzZ

wherein R R R, A, and Z are as defined above.

It is also within the contemplation of the present invention that thesteroids of Formulae I-VI may have substituents or unsaturatedcarbon-carbon bonds other than those specifically depicted. For example,a lower alkyl group may be present on the l-, 7-, or l6-positions, ahydroxy or lower acyloxy group may be present in the l-, 11-, 16-, orl7-positions, and double bonds may be present in the 1(2)- and/or the 3(4)- positions.

The production of ,SB-H-steroids of the type defined by Formulae II, IH,and VI is unexpected in view of the teachings of A. Schubert, J. Org.Chem.,26, 159 (1964); H, B. Henbest, J. Chem. Soc., 1957, 4596 and 4765;and N. L. Allenger, J. Org. Chem.-, 26, 3626 (1961). These publicationsdisclose that 5 3-H-6-ketosteroids which are unsubstituted in the2-position are isomerized under acidic or basic conditions to thecorresponding 5a-H- steroids, thus leading to the conclusion that the,A/B- trans-ring linkage is the more stable form for 6-ketosteroids.Unexpectedly, ithas been discovered by this invention that -ketosteroidssubstituted in both the 2- and 3-positions with hydroxy groups or esterified or etherified hydroxy groups and having an A/B-cis-ringlinkage are stable. t

The various products of this invention are obtained by both known andnovel reactions from known starting mateirals, such as A-cholesten-6-one, methyl 3,3-ethylenedioxy-A -pregnen-20-carboxylate,3-hydroxy-A' -cholesten- 6-one, 3-acetoXy-A -erg0stadien-6-one,3a-hydroxy-20, ZO-ethylenedioxy-Sa-H-pregnan-6-one, 3,3-ethylenedioxy-20-hydroxymethyl-A pregnen, and the like.

A major novel reaction employed in producing the products of thisinvention comprises the conversion of a25,3-dihydroxy-5u-H-6-ketosteroid or a monoor diester or monoor dietherthereof to the corresponding 55-H- compound; i.e., by effectingisomerization at the 5-position, as is illustrated by Equation A,employing partial formulas for starting material and product:

flu 0 wherein B represents the remainder of the steriod nucleus. Thisprocess is particularly useful for producing a compound of Formula IIabove from the corresponding Sa-H-steroid.

The isomerization is effected by the introduction of energy such as bythermal energy, irradiation, and the like, preferably in the presence ofan inert organic solvent. Suitable solvents include alcohols such asmethanol and ethanol; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, and dioxane; ketones such as acetone and methyl ethylketone; esters such as ethyl acetate; hydrocarbons such as benzene;chlorinated hydrocarbons such as chloroform; and the like.

The introduction of thermal energy is effected by heating at elevatedtemperatures, such as at about 50 C. or higher, and preferably in therange of from about 60 to about C. The presence of acidic or basiccatalysts, heretofore known as isomerization catalysts, promotes therate of isomerization and permits the use of lowertemperatures. Suitableacid catalysts include sulfuric acid, perchloric acid, selenousacid,p-toluene-sulfonic acid, and Lewis acids such as boron trifluoride,magnesium bromide, mercury chloride, aluminum chloride, and the like.Basic catalysts which can be employed include inorganic bases such asalkali metal hydroxides, for example, sodium hydroxide or potassiumhydroxide, and alkaline earth metal hydroxides, for example, calciumhydroxide or magnesium hydroxide; as well as basic'salts such aspotassium carbonate, and the like; and organic bases such astriethylamine, benzyltrimethylammonium hydroxide,

pyridine or lutidine. In addition, acidic or basic adsorption agentssuch-as aluminum oxide or silica gel will also catalyze theisomerization.

The'acidic or'basio reaction medium, in addition to cata'lyzing theisomerization at the S position, can also be employed to promote otherstructural changes in the steroid. For example, selenium dioxide(selenous acid), 'Which is employed to introduce a hydroxy group in theI la-position, as hereinafter described, is sufficiently acidic i toeifect isomeriztaionof the Set-hydrogen to the 5js=hydrogen.-

--..The temperature and reaction time necessary to achievethe-isomerization will vary depending upon the catalyst, butsuitabletemperatures and times can be readily determined-.cby thesehaving ordinary skill in the art. For example, at 60-80 C. times ofabout4 hours are normally employed when hydrochloric acid is employed as thecatalyst, Whereas about 1 hour is suflicient when potassium'hydroxide isemployed. On the other hand, isomeriiation occursat .C..in less than 1hour when boron trifluorideisthegcatalyst..

The isomerization of this invention may also be effected by the use ofultraviolet'radiatiom-by which term is meant light having a wave lengthof less than about 4000 angstrom units. I

The product of the isomerization, if conducted for a sufiicient lengthof time, is an equilibrium mixture of the Soc-H- and SB-H-isomers inapproximately equimolar amounts. At short times and/or with weakcatalysts, less than an equimolar ratio of /3-H- to 5a-H-steroid isproduced These isomers may be separated, however, by techniqueslmownt'o' the art such as chromatography, fractional crystallization,and the like. In addition, when the isomerization product: is a25,3.5-dihydroxy compound, the isomers may beseparated by reaction withacetic anhydride. The SB-H-isomer readily forms a 219,313-acetate,whereas the Sa -H-isomer forms a 2fi-hydroxy-3p-acetate. The diace'tateis normally less soluble than the mono-acetate and thus can be readilyprecipitated from the reaction mixture. The Su-H-mondacetate, whichremains in solution, can then 'be subjected to a second isomerization inaccordance with this invention. H

The products of this process can be hydrolyzed or acylated,if-de'sired,by -known reaction techniques. Furthermore, compounds wherein R and Rwhen taken together'are aikyIenediOXY, are readily formed by theacidcatalyiedreaction of a 2,8,3/3-dihydroxy compound with a ketone,for. example, acetone.

"second"novelreaction of this invention, and one' which-is related tothe above-described isomerization, comprises {the conversion of a2;8,3-dihydroxy-5a-H-6- keto-A' -steroid'which is unsubstituted in thel4-position or a mono on'diether or mono"o'r diester thereof to thecorresponding"SB H-l'4t-hydroxysteroid, as is illustrated byEquationB:--

Equwti'on B This reaction is effected by the use of selenium dioxide,and is normally conducted in an inert solvent such as those discussedabove. The reaction temperature is not narrowly criticahalthougheleyated temperatures, preferably of a wt 1t ta t 07 are 1 orm y-e p yedThe product 5fl-H-l4a-hydroxysteroid is recovered from the reactionmedium by conventional techniques.

Still another novel technique for producing2,8,3-dihydroxy-Sfl-H-6-ketosteroids or monoor diethers or monoordiesters thereof comprises the acid-catalyzed isomerization of acorresponding 5,6-oxidosteroid, as is illustrated by Equation C:

Equation C:

CH /R 051 R CH CH R V R RZ/vw V R2-w a H l O O The oxirano ring of thestarting material of this process may be in either the aorfl-orientation. Suitable acid catalysts are those discussed above withreference to the Su-H- to Sfi-H-isomerization. This reaction is normallyeifected in the presence ofan inert organic solvent such as thosediscussed above. The reaction temperature is not narrowly critical,although it is preferred to employ relatively low temperatures,especially those in the range of from about -l0 C. to about +30 C.

Still another novel transformation useful in producing a2B,SB-dihydroxy-SB-H-G-ketosteroid is that proceeding from a3,6-dioxo-5a-H-steroid by a series of reactions illustrated by EquationsD, E, and F, employing partial formulas:

The reaction steps outlined above are novel and yield unexpected resultsboth individually and in combination. This sequence is especiallyvaluable for producing compounds of Formula II wherein A represents asingle bond.

In the first step of this reaction sequence (Equation D), a 3,6 dioxo 5aH steroid is brominated by generally known techniques to produce a2a-brorno-3,6-dioxo-5ot- H-steroid. This result is unexpected in view ofthe disclosure of L. H. Sarett, J. Org. Chem.'8, 405 (1943) that thebromination of 3,6-choIanedione, a Sfl-H-steroid, yields a mixture ofpolybromo compounds.

The bromination of this invention is effected by reacting the3,6-diketosteroid with bromine in any suitable manner. A preferredprocedure comprises dissolving the 3,6-ketosteroid in a solvent which isinert towards bromine, such as tetrahydrofuran, dioxane, ether, benzene,or chloroform, and subsequently adding to this solution a solution ofbromine in acetic acid dropwise at reduced temperature, i.e., belowabout room temperature (2025 C.). On completion of the bromination, freehydrogen bromide produced by the reaction is neutralized, as by theaddition of a buffer such as potassium acetate.

In the second step of this novel reaction sequence (Equation E), the3-keto group of the 2a-bromo-3,6- diketosteroid is selectively reducedby reaction of the steroid with a lithium tri(lower alkoxy)aluminumhydride, preferably a lithium tri(tert.-lower alkoxy)aluminum hydride,such as lithium tri(tert.-butoxy)aluminum hydride or lithiumtri(tert.-amyloxy)aluminum hydride. This reduction is effected in aninert organic solvent such as dioxane, tetrahydrofuran, or ether, and ispreferably effected at reduced temperatures, especially in the range offrom about 5 to about C. The production of a 35-hydroxy-6-ketosteroid inthis manner is entirely unexpected, for it could not be foreseen thatthe 3,6-diketo system would be susceptible to selective reduction.Furthermore, if one were to predict which of the two keto groups wouldbe more likely to be reduced, the freestanding 6-keto group would appearto be the most susceptible to preferential reduction. This is becauseattack at the 3-keto group by the bulky lithium tri(lower alkoxy)aluminum hydride compounds would be expected to be sterically hinderedby the 2a-bromo atom.

The final reaction step of this sequence (Equation F) comprises thereplacement of the Zu-bromo atom with a Zfi-acyloxy group, employinggenerally known techniques but leading to the unexpected 5fi-H-steroids.In a preferred technique, the 2a-bromo-3fi-hydroxysteroid produced bythe above-described selective reduction is esterified to form a2a-bromo-3fl-acyloxysteroid, which is then reacted with an alkali metalacylate or a silver acylate, preferably an acetate, and most desirablysilver acetate This reaction is normally effected at elevatedtemperatures, preferably in the range of from about 75 C. to about 125C. As with the previously described Soc-H- to Sfi-H-isomerization, theproduct of this reaction is a mixture of 5aand Sfl-H-isomers, which maybe readily separated by known techniques.

A further novel reaction sequence of this invention comprises theconversion of a 25,3;8-dihydroxy-6-keto- A' -pregnen--carboxylic acid tothe corresponding aldehyde, as is illustrated by Equation G:

Equation G:

on, com

This conversion is effected by first reacting the acid, the hydroxygroups of which are preferably protected, as by conversion to acyloxy,alkoxy, or alkylenedioxy groups, with carbonyl diimidazole in accordancewith known procedures to form an imidazolide. This product is thenreacted with a lithium tri(lower alkoxy)aluminum hydride to effectselective conversion of the imidazolide group to the formyl group. Thisreaction is unexpected because the normally used reducing agent, lithiumaluminum hydride, is known to effect reduction of keto groups andelimination of ester groups. The reaction is preferably conducted in theabsence of free oxygen, as in an argon or nitrogen atmosphere. Thereaction temperature is not narrowly critical, although temperatures ofabout room temperature (2025 C.) are normally employed. The reaction isgenerally effected in the presence of an inert organic solvent such asthose previously discussed above. a i I A final novel process of thepresent invention comprises the conversion of a 20-formylpregnan-6-oneto a 20-(1- hydroxyhydrocarbyl)pregnan-6-one, as is illustrated byEquation H: 1 1 I y Equation Hi OH CH; CH0 7 on; on; R

O This reaction is effected byreacting the ZO-formyl compound with aGrignard reagent having the formula; v

R MgX v wherein R is as defined above and. X is chlorine, bromine, oriodine. This conversion is effected the presence of an inert solventsuch as those previously disclosed and preferably an ether such astetrahydrofuran, ether, dioxane, or the like. ,The temperature of thereaction is not narrowly critical, but reduced temperatures preferablyin the range of from about 5 toabout 3-15" C. and more especially about0-5 C., are employed to ensure as quantitative and selective a reactionas possible. In a preferred technique, a solution of the Grignardreagent is slowly added with stirring to asolution of the 20-formylcompound. The selective reaction with the 20- formyl group withoutattack on the 6-keto group or an acyl group is unexpected, for it iswell known that Grignard reagents readily react with such groups. Thereaction time is not narrowly critical, and the reaction is generallycomplete after about 5 to 10 minutes under the foregoing conditions.However, the reaction period can be permitted to extend as long as about30 or even about 60 minutes without the occurrence of significant sidereactions. I

When R is an unsaturated group, the unsaturated side chain may beselectively hydrogenated over a metal catalyst, such as palladium, andpreferably platinum dioxide, employed as such or deposited onconventional supports. The hydrogenation is preferably effected in asolvent for the steroid such as a lower alcohol, for example, methanolor ethanol; an ether, for example, diethyl ether, dioxane, ortetrahydrofuran; an ester, for example, ethyl acetate; or a hydrocarbon,for example, benzene. Carboxylic acids, such as acetic acid, are notdesirable because they promote the reduction of the 6-keto group as wellas the A' -bond, if-presentw When a l4a-hydroxy compound is desired asthe product, the hydrogenation should be effected prior to theintroduction of the l4a-hydroxy' group because of the tendency of thehydrogenation. to effect at least partial eliminationofthis group.Alternatively, the Grignard reaction may be effected with a reagentwherein R is already saturated. n i

, -The 14u-hydroxylation maybe effected by known techniques, as well asby the previously described reaction with selenous acid, which may beeffected with either a Soc-H- or a 55-H-steroid. Additionally,14a-hydroxylation may be effected by biochemical methods, as by theaction of microorganisms and/or the enzymes formed bythem. Suitablesystemsinclude enzymes of the type Curvularia, preferably Curvulariailunata, the type Absidia, preferably Absz'dia regnieri, and especiallyof the type Heliocostylum, preferably Heliacostylum piriforme, or thetype Mucor, preferably Mucor griseo cyanus.

As indicated above, the various products of this in vention possessactivity as insect metamorphosis hormones. Thus, the products ofthisinvention may be employed to induce insect metamorphosis at a pointin time which is detrimental to the further population of the insect.Because of the hormonal nature of these products, a resistance to theiraction cannot develop, thus avoiding a significant disadvantage ofconventional insecticides. In addition to their metamorphosis-inducingactivity, the products of this invention possess a" profound influenceon the cell metabolism in other animals, especially in warmbloodedanimals or crustaceans. For example, by the use of the products of thisinvention, it is possible to induce the moulting stage in crustaceans,thus rendering them suitable as fish' bait. Additionally, the productsof thisinventioncan be employed to control crustacean infestation anadthe damage caused thereby by inducing the moulting' stage and exposingthe crustacean to natural decimation."Furthermore, the products of thisinvention havebeen observed to have central nervous system activity. Itis thus readily aparent that the products of this invention have wideutility as pharmaceuticals in hormone and veterinary medicine as well asuse as agents for the control of insects in agricultural applications.Furthermore, many of the products of this invention serve asintermediates for the manufacture of still other valuable medicinal oragricultural agents.

The products of this invention can be employed in the form ofpreparations which contain them in admixture with suitable organic orinorganic inert carrier materials such as, forexample, water, starch,magnesium sterate,

talc, vegetable oils, polyalkylene glycol, or the like. Thefollowingexamples are illustrative. For convenience in following the reactionsequences employed, each example is limited to the production ofderivatives of a single known starting material, :but may illustrate theproduction of several of the products of this invention as well as theuse of one or more of the novel processes of this invention. It is to beunderstood, however, that these examples are not limited to the specificstarting materials or sequences employed, and that other startingmaterials and reactions known to the art may be used where desired. 1EXAMPLE'I From A -cholesten-6-one.(A) Synthesis of 25-acetoxy-35-hydroxy-5wcholestan-o-one To a solution of 2 grams of 50: Acholesten-6-one in 270 milliliters of glacial acetic acid and 3.7milliliters of water, there was added 3.2 grams of silver acetate and,with intensive stirring, 1.9 grams of iodine. The resulting reactionmixture was heated with stirring at 45 C. for 3 hours, treated with anexcess of common salt, stirredfor an additional 5 minutes, and thenfiltered. The deep red filtrate was then evaporated to dryness undervacuum and the residue was taken up methyl acetate, washed in sequencewith water, thiosulfate solution, and again with water, dried oversodium sulfate, and concentrated to obtain 25 acetoxy 35 hydroxy-Sawho-10 lestan-6-one, melting point 2172l8 C. (from methylenechloride/acetonitrile). r r (B) Synthesis of 25,35-dil1ydroxy-Sa-cholestan- "f I V 6-one (C) Synthesis of 25,35diacetoxyand 25,35 dihydroxy 55 cholestan 6 one.-(1) =From 25,35-dihydroxy-5a-cholestan-6-one (a) Acid-catalyzed reaction. A solution of500 milligrams of 25,35 dihydroxy 5a cholestan 6 one in 20 millilitersof ethanol and 5 milliliters of 3 N hydrochloric acid was heated atboiling for 4 hours. After cooling and dilution with water, the reactionsolution was extracted with chloroform. The extract was washed withwater, dried over sodium sulfate and concentrated in vacuum to yield25,35-dihydroxycholestan-6-one as an approximately equimolar mixture ofthe Su-H- and 55-H- isomers.

(b) Base-catalyzed reaction-A mixture of 600 milligrams of 25,35dihydroxy 5a cholestan 6 one, 500 milligrams of potassium hydroxide and10 milliliters of methanol was heated at reflux for one hour. Aftercooling, the reaction mixture was treated with water and extracted withchloroform. After workup of the extract, there was obtained25,35-dihydroxycholestan 6 one as an approximately equimolar mixture ofthe Sa-H- and 55-H-isomers.

(2) From 2 5-acetoxy-3 5-hydroxy-5 Ot'ChOlCStBJI- 6-one (a)Acid-catalyzed 'reaction.-A solution of 1 gram of 25 acetoxy 35 hydroxy5a cholestan 6 one in 40 milliliters of ethanol and 10 milliliters of 3N hydrochloric acid was heated at reflux for 4 hours. After cooling, thereaction mixture was diluted with water and extracted with ethylacetate. The extract was worked up to yield 25,35 'dihydroxycholestan 6one as an approximately equimolar mixture of the Su-H- and 55-H-isomers.

(b) Base-catalyzed reaction.A mixture of -1 gram of 25 acetoxy 35hydroxy 50c cholestan 6 one and 1 gram of potassium hydroxide in 20milliliters of methanol was heated at reflux for 2 hours. After cooling,the reaction mixture was diluted with water and extracted with ethylacetate. After workup of the extract, there was obtained 25,35dihydroxycholestan 6 one as an approximately equimolar mixture of theSa-H- and 55- H-isomers. v

(3) Isolation of 25,35-diacetoxy-55-cholestan- 6-one A solution of 1gram of 25,35 dihydroxycholestan-6- one 5 H isomeric mixture produced asdescribed above in 20 milliliters of acetic anhydride and 10 millilitersof pyridine was allowed to stand overnight at. room temperature. Afterthe addition of ice and extraction with chloroform, v the extract waswashed first with dilute hydrochloric acid and then water. The extractwas then dried over sodium sulfate and concentrated in vacuum to yield25,35 diacetoxy 5 5 cholestan '6 one, melting point 148149 C. (frompetroleum ether). Y

.(4) Isolation of 25,35-dihydroxy-55-cholestan-6-one A solution of 1gram of 25,35-diacetoxy-55-cholestan- 6-one in milliliters of absolutemethanol was treated 1 1 with 0.5 gram of potassium carbonate andstirred overnight at room temperature. The resulting reaction mixturewas poured into water and extracted with chloroform. After workup of theextract, there was obtained 2,8,3B-dihydroxy- S-cholestan-6-one, meltingpoint 167- 16 8 C. (from acetonitrile and acetone).

" (D) Synthesis of 25,3B-isopropylidenedioxy-5pcholestau-6-one From3fl-hydroxy-n' -cholesten-6-one.-(A) Synthesis of 23-acetoxy-3p-hydroxy-5a-A -cholesten-6-one A mixture of 11 grams of 38-hydroxy-Sa-N-cholesten- 6-one, grams of p-toluenesulfonic acid, and250 milliliters of pyridine was stirred at room temperature for 24 hoursand then poured into ice water. The precipitate which formed wasfiltered off and dissolved in methylene chloride. The resulting solutionwas washed with water, dried over sodium sulfate and evaporated todryness. Upon recrystallization of the residue from diisopropyl ether,there was obtained 3fi-tosyloxy-Sa-A' -cholesten-6-0ne, melting point153-154 C.

A mixture of 4 grams of 3fl-tosyloxy-5a-A -cholesten- 6-one, 1 gram oflithium bromide, 1.5 grams of lithium carbonate, and 200 milliliters ofdimethylformamide was heated at 120 C. for 5 hours. After cooling, thereaction mixture was poured into ice water and weakly acidified withhydrochloric acid. The resulting precipitate was filtered off anddissolved in methylene chloride. The resulting solution was washed withwater, dried and concentrated to yield 5a-A -cholestadien-6-one.

The thus-produced Six-A "-cholestadien-6-one was dissolved in 250milliliters of acetic acid at 60 C. Thereafter, there was added insequence 3.9 milliliters of water, 3.1 grams of silver acetate, and 2grams of finely ground iodine. The resulting reaction mixture was heatedat 60 C. with vigorous stirring for 5 hours. After treating with anexcess of common salt and stirring for an additional 5 4 minutes, thereaction mixture was filtered. The deep red filtrate was concentrated todryness under vacuum. The residue was taken up in ether and the ethersolution was washed with water, bicarbonate solution, and again withwater, and then dried and concentrated. After recrystallization of theresidue from diisopropyl ether, there was obtained Zfi-acetoxy 3 3hydroxy-Sa-A -cholesten-6-one, melting point 2152l7.5 C.

(B) Synthesis of 2B,3p-hydroxy-Sa-A -cholesten-6-one A mixture of 1 gramof 2fi-acetoxy-3B-hydrOXy-Sa-A' cholesten- -one and 1 gram of potassiumcarbonate in 100 milliliters of methanol was stirred at room temperaturefor 40 minutes. After pouring the resulting reaction mixture into water,the precipitate which had formed was filtered off and dissolved inmethylene chloride. Workup of this solution gave 25,2;3-dihydroxy-Su-A-cholesten-6- one, melting point 208210 C. (from acetone).

(a) Acid-catalyzed reaction.A mixture of 500 milligrams of2p,3p-dihydrOXy-Sa-A' cholesten-6-one in milliliters of ethanol and 5milliliters of 3 N hydrochloric acid was heated at boiling for 20 hours.After cooling, the mixture was poured into ice water and the precipitatewhich formed was separated and taken up in methylene chloride. Theorganic solution was washed with water, dried with sodium sulfate andconcentrated in vacuum. On recrystallization of the residue fromdiisopropyl ether, there was obtained 25,3[3-dihydroxy-A'cholesten-6-one as an approximately equimolar mixture of the'Sa-H- andSIi-H-isomers.

(b) Base-catalyzed reaction.A mixture of 500 milligrams of25,3{3-dihydroxy-5a-A -cholesten-6-one, 500 milligrams of potassiumhydroxide'and 2O milliliters of methanol was heated under reflux for 2hours. After cooling, pouring the reaction mixture into ice water andworkup of the resulting precipitate as described above, there wasobtained 2,8,3 3-dihydroxy-A -cholesten-6-one as a mixture of the Sa-H-and SB-H-isomers.

(2) From 23 acetoxy-3,9-hydroxy-5a-A -cholesten-6-one (a) Acid-catalyzedreaction.A mixture of 1 gram of 2fl-acetoxy-3/3-hydroxy-5a-A-cholesten-6-one in 50 milliliters of ethanol and 10 milliliters of 3 Nhydrochloric acid was heated at boiling for 20 hours. After cooling andpouring the reaction mixture into ice water, the precipitate which hadformed was separated and taken up in methylene chloride. After workup ofthe organic solution, there was obtained213,3fi-dihydroxy-N-cholesten-6-one as a mixture of the Sa-H- andSB-H-isomers.

(b) Base-catalyzed reaction.A mixture of 500 milligrams of ZB-acetoxyhydroxy-5a-A -cholesten-6-one and 500 milligrams of potassium hydroxidein 30 milliliters of methanol was heated under reflux for 4 hours. Aftercooling the reaction mixture and pouring it into ice water, theprecipitate which had formed was separated out and worked up asdescribed above to obtain 25,33- dihydroxy-A' -cholesten-G-one as amixture of the SOL-H- and 5fi-H-isomers.

(3) Isolation of 2B,3 8-diacetoxy-5fi-A -cholesten-6-one A solution of 1gram of 25,3B-dihydroxy-N-cholesten- 6-one-5-H-isomeric mixture producedas described above in 30 milliliters of acetic anhydride and 15milliliters of pyridine was held at room temperature for 4 hours. Theresulting reaction mixture was poured into ice water and extracted withmethylene chloride. The organic extract was washed with dilute sulfuricacid and water, dried and concentrated. After recrystallization frompentane, there was obtained 25,318-diacetoxy-5fl-A -cholesten-6-one,melting point 166168 C.

(4) Production of Zfl,35-dihydroxy-Sfl-N-cholesten- 6-one A mixture of 1gram of 2B,Bfl-diacetoxy-Sfi-N-cholesten-6-one, 1 gram of potassiumcarbonate, and 100 milliliters of methanol was stirred at roomtemperature f0 r40 minutes. The resulting reaction mixture was pouredinto water and the aqueous mixture was extracted with methylenechloride. The organic phase was washed with water, dried, andconcentrated to obtain 25,3[3-dihydroxy- SB-N-cholesten-G-one, meltingpoint 207209 C. (from diisopropyl ether).

(D) Synthesis of 2,8,3fl-isopropylidene-Sfi-A -cholesten- 6-one Asolution of 400 milligrams of ZflJB-dihydroxy-Sa-N- cholesten-6-one inmilliliters of acetone was cooled to 0 C., treated with one drop ofboron trifluoride etherate and held at 0 C. for 15 minutes. Theresulting reaction mixture was poured into water, extracted withmethylene chloride, and the methylene chloride phase was washed withwater, dried and concentrated to obtain 25,3B-isopropylidenedioxy-5fi-A'-cholesten-6-one, melting point 163l63.5 C. (from methanol).

(E) Synthesis of 213,313,14ot-trihydroxy-B-n' -cholesten-6- one.-(1)Introductionof the 14a-hydroxy group folv lowed'by isomerization IEmploying procedures similar tothose described in Example IA(3),2Q-acetoxy-3fi-hydroxy-A -cholesten-6-one was acetylated to 2B,3fldiacetoxy-5a-A -cholesten-6-one, melting point 196-198 C. (frommethanol). Employing techniques similar to thosedescribed in Example IVbelow, this product was reacted with selenium dioxide in dioxane toproduce -2p,3B-diacetoxy-14a-hydroxy5a-A cholesten-6-one, melting point231 232 C. (from methanol); Employing procedures similar to thosedescribed in Example IC(Z), the thus-obtained product was isomerizedwith potassium hydroxide in methanol. After workup there was obtained253B,14d-trihydroxy-5B-A' -cholesten-6-one, melting point 207-209 C.(from ether/hexane).

In the manner described in Example IC(3) above, the

above-obtained 213,35,14u-trihydroxy-compound was reacted with aceticanhydride in pyridine to produce 2 3,35- diacetoxy-14a-hydroxy-5p n'-cholesten 6 one, melting point 189191.'C. (from isopropyl ether).

'7 2) Simultaneous .1 4nthydroxylation and isomerization vacuum andmixed with water. The precipitate which formed Was separatedand-dissolved in methylene chloride. The resulting organic solution waswashed with water, dried over sodium sulfate and evaporated to obtain218 acetoxy-3fl,14a-dihydroxy-Sfl-A' cholesten-6-one, melting point260-261? C. (from diethyl ether).

EXAMPLE III From 3fl-acetoxy-A' -ergostadien-6-one.(A) Synthe- A mixtureof 11.7. grams of 3fi acetoxy-A' -5a-ergostadien-6 -one, 11.7 grams ofpotassium carbonate and 2 liters of methanol was heated at boiling for30 minutes. The resulting reaction mixture, after cooling, was pouredinto water and the organic phase was washed, dried, and concentrated.

The crudesaponification product, in admixture with 200 milliliters ofpyridine and 13.5 grams of p-toluenesulfonyl chloride, .was held at roomtemperature for 24 ,hours. After dilution of. thereaction mixture withwater, .the precipitate which had formed was separated off and'dissolvedin methylene chloride. The organic solution was washed,rdied'and concentrated to yield 3,8-tosyloxy-A' 5 &-ergostadien-'6-on'ewhich, after crystallization from diiS opropyl ether m'elted at 148-149C.

I A. mixture of 2.2 gramsof 3,8-tosyloxy-A -5a-ergostadien-o one ini 10milliliters of dimethylaniline was heated at 200" C., for l rninutejs'.iAftercooling, the reaction solutionwasjpoiiredlinto dilute sulfuricacid, and the pre- J cipitatefwhich'formed was filtered'otf by suctionand taken 1'lp in chloroform. The organic solution was washed untilAfter dissolvingftheicrude product in 130 milliliters of 'acetic acidat' 45"? C;,' there was successively added 2.1

milliliters of water, 1.8 grams of silver acetateand 1.09 gramsof'finely powdered iodine, The resulting mixture was heated withvigorous stirring ati45 C. for 50 minutes. After the addition ofanexcess of common salt, the reaction mixture waslstirredf fo'r anadditional 5 minutes, filtered ancl'the filtrate concentrated to drynessin vacuum. Thei'relsidue was purified" yfpreparative thin layer chro-'hy,"'and after recrystallization from diisopropyl ether, there wasobtained Zfl-acetoxy-3fl-hydroxy-A' -5aergostadien-6-one, melting point208-210 C.

(B) Synthesis of 2,8,3 3-dihydroxyand 25,35-diacetoxy- 5fi-A-ergostadiene-6-one A solution of 2.1 grams of2,B-acetoxy-3fl-hydroxy-A' 5a-ergostadien-6-one in 100 milliliters ofethanol and 20 milliliters of 3 N hydrochloric acid was heated atboiling for 20 hours. After cooling, the reaction mixture was dilutedwith water and the precipitate which formed was separated and taken upin methylene chloride. The organic solution was washed with water, driedover sodium sulfate and concentrated in vacuum to obtain2fl,3fi-dihydroxy- A -Sfl-ergostadien-G-one as an oil.

The diol was acetylated at room temperature for 1 6 hours by reactionwith 5 milliliters of pyridine and 2.5 milliliters of acetic anhydride.The resulting reaction mixture was diluted with water and theprecipitate which formed was filtered off and dissolved in methylenechloride. After washing until neutral, the organic solution was driedand concentrated in vacuum to yield 25,3;8-diacetoxy-A'-5B-ergostadien-6-one, melting point 148- 150 C. (from acetone/ hexane).

(C) Synthesis of 2B,3fi-diacetoxy-14a-hydroxy- SB-A" -ergostadien-6-oneA solution of 5.8 grams of 2,8-acetoxy-3fi-hydroxy-5a- A'-ergostadien-6-one in 80 milliliters each of absolute pyridine andacetic anhydride was allowed to stand at room temperature overnight andthen was decomposed with ice water, and extracted with chloroform. Theextracts were washed until neutral and evaporated to yield2B,3}8-diacetoxy-5a-A' -ergostadien-6-one, melting point 195-196" C.(from methanol).

A solution of 3 grams of 25,3/8-diacetoxy-5a-A -ergostadien-6-one in 120milliliters of absolute dioxane was heated to 80 in an inert atmosphere.After the addition of 6.1 grams of selenium dioxide, the reactionmixture was stirred for 15 minutes, filtered, diluted with water andextracted with ether. The extract was washed with water and the solventevaporated. The residue was chromatographed on 100 grams of alumina,using benzene containing 10 percent of ether as the eluting agent, toobtain 213,3fi-diacetoxy-14a-hydroxy-5a-A -erogstadien- 6-one, meltingpoint after recrystallization from isopropyl ether, 226-227 C.

A mixture of 1.3 grams of 25,3 8-diacetoxy-14u-hydroxy-Sa-A-ergostadien-6-one, 60 milliliters of methanol, 5 milliliters of waterand 0.5 gram of potassium carbonate was heated at boiling overnight inan inert atmosphere. The reaction mixture was then diluted with waterand extracted with chloroform. The extract was washed until neutral,dried and evaporated. The crude reaction product was reacted with aceticanhydride in pyridine according to the procedure described in ExampleIC( 3). After Workup, the crude product was chromatographed on 30 gramsof alumina. Elution with benzeneether (1:1) yielded25,3;8-diacetoxy-l4u-hydroxy-5B-A ergostadien6-one, melting point202-203 C. (from methanol).

In an alternative procedure a mixture of 1 gram ofZB-acetoxy-3fi-hydroxy 5a A ergostadien-G-one, 2 grams of seleniumdioxide and 30 milliliters of absolute dioxane is stirred at roomtemperaturefor 24 hours. The reaction mixture was filtered and thefiltrate was stirred with 0.5 gram of deactivated Raney nickel. Afterfiltration and evaporation, there was obtained ZB-acetoxy-3fi,14a-dihydroxy 5a A ergostadien-6-one, melting point 254-256 C.(decornp.) (from acetonitrile).

A solution of 600 milligrams of 2;8-acetoxy-3B,14a-dihydroxy-Sa-A'-ergostadien-G-one in 45 milliliters of methanol and 5 milliliters ofWater was treated with 250 milligrams of potassium carbonate accordingto the procedure described above. After workup, there was obtained2,8,3B-diacetoxy-14 hydroxy-SB-N' -ergostadien- 15 6-one, which isidentical with the product produced as described above.

(D) Synthesis of (22R),2B,3B,l4a,22,25-pentahydroxy- 3-A'-cholesten6-one (ecdyson) A solution of 4 grams of 25,35-diacetoxy-5a-A'-ergostadien-6-one (produced as described in part C above) in 750milliliters of methylene chloride and 500 milliliters of methanol wastreated at 70 C. over a 75-minute period with 10 millimols of ozonewhich was supplied in an oxygen stream. After the addition ofmilliliters of trimethoxyphosphine, the mixture was stirred for 30minutes, then decomposed with water and extracted with ether. Processingof the ether extracts afforded a crude product which was quicklychromatographed on alumina to obtain (S),25,3B-diacetoxy-ZO-formyl-Six-A-pregnen-6-one, melting point 2l12l2 C. (from methylene chloride-ether)To a solution of ethyl magnesium bromide (prepared from 2 grams ofmagnesium and 6.4 milliliters of ethyl bromide in 100 milliliters ofether), there was added dropwise a solution of 16 milliliters of2-methyl-2-tetrahydropyranyloxy-3-butyne in 100 milliliters oftetrahydrofuran. The reaction solution was stirred for 30 minutes atroom temperature and then added dropwise with stirring to a solution of4.7 grams of (2OS),2fl,3[3-diacetoxy- 20-formyl-5wA' pregnen-6-one in200 milliliters of tetrahydrofuran at l0 C. The temperature of thereaction mixture was allowed to rise to 0 C., whereupon the mixture wasdecomposed by the addition of ammonium chloride solution. Extractionwith ether afforded a crude product which was chromatographed on 200grams of alumina. The fractions obtained by elution with 2 liters ofbenzene-petroleum ether (1:1) were discarded. The product was theneluted with chloroform containing 10 percent of methanol and againchromatographed on 140 grams of alumina. After removal of undesiredby-products, the(22R),25,3fi-diacetoxy-22-hydroxy-25-(tetrahydropyran-Z-yloxy) 50c Acholesten-Z-yn-6-one was eluted with benzene and benzene containing 1percent of ether. Melting point 188 C. (from isopropyl ether).

A solution of 3 grams of (22R),2B,3fl-diacetoxy-22-hydroxy--(tetrahydropyran-Z-yloxy)-5u-A -cholesten 23- yn-6-one in 50 millilitersof methanol was hydrogenated in the presence of 200 milligrams ofprehydrogenated platinum until the uptake of 75 milliliters of hydrogen.After workup there was obtained (22R),2 3,3 3-diacetoxy- 22-hydroxy-25-(tetrahydropyran-Z-yloxy)Sa-A" cholesten-6-one, melting point 155156 C.(from isopropyl ether.)

A solution of 3 grams of(22R),2;3,3B-diacetoxy-22-hydroxy-25-(tetrahydropyran 2yloxy)Sa-N-cholesten-G- one in 150 milliliters of absolute dioxane wasstirred with 6 grams of selenium dioxide at 20 C. for 15 hours. Thesuspension was filtered, and 1 gram of deactivated Raney nickel wasadded to the filtrate. After stirring for minutes and filtration, thesolution was diluted with chloroform, washed with water and evaporated.Recrystallization of the residue from ether afforded(22R),2;8,3B-diacetoxy 1401,22 dihydroxy 25(tetrahydropyran-Z-yloxy)-5a-A' -cholesten6-0ne, melting point 194195 C.

A solution of 1 gram of (22R),2B,3;3-diacetoxy-14a,22dihydroxy-25(tetrahydropyran-Z-yloxy)-5-A" cholesten- 6-one and 200milligrams of potassium carbonate in 20 milliliters of methanol washeated to reflux for 2 hours. The reaction mixture was diluted wtih 200milliliters of ethyl acetate, washed with saturated brine, dried andevaporated. The residue was dissolved in 16 milliliters of methanol, andallowed to stand with 4 milliliters of 2 N hydrochloric acid for 15minutes at room temperature. The mixture was then neutralized with 8milliliters of 1 N sodium hydroxide and, after the addition of ethanol,evaporated to dryness. The residue was dissolved in tetrahydrofuran andthe resulting solution was filtered and evaporated. The residue wasdissolved in 16 milliliters 16 afforded(22R),2fl,3/8,l405,22,25-pentahydroxy-5fiA cholesten-6-one, meltingpoint 233 C. (decomp.). Melting point after further recrystallizationfrom methanol-acetone, 241 C. (decomp.).

(E) Synthesis of 3B-acetoxy-22-hydroxy-25-(tetrahydropyran-Z-yloxy)-5-A-cholesten-23yn-6-one Employing procedures similar to those describedabove, 3B-acetoxy-A' -5ot-ergostadien-6-one was subjected to ozonolysisto produce 3p-acetoxy-20-formyl-5a-A -pregnen-6-one.

To an ethyl magnesium bromide solution [produced from 244 milligrams ofmagnesium and 0.84 milliliter of ethyl bromide in 15 milliliters ofether], there was added dropwise a solution of 1.93 milliliters of2-methyl-2- tetrahydropyranyloxy-Sbutyne in 10 milliliters oftetrahydrofuran, and the resulting mixture was stirred for one hour atroom temperature. The resulting solution was cooled to 0-5 C. and therewas addeda solution of 386.5 milligrams of 3fi-acetaoxy-20-formyl-5a-A-pregnen-6-one in 10 milliliters of tetrahydrofuran. The resultingmixture was stirred for 45 minutes and then mixed with saturatedammonium chloride solution. After taking'the product up in ether, it waswashed with saturated salt solution, dried and evaporated. Afterchromatographing on silica gel, there was obtained3.5-acetoxy-22-hydroxy-25-(tetrahydroxypyran-Z-yloxy)-5a-A"-cholesten-23-yn 6-one, melting point 175-178 C. (fromhexane/ether).

EXAMPLE IV From methyl 3,3ethylenedioxy-A -pregnene-20 carboxylate.(A)Synthesis of methyl 3,3-ethylenedioxy-5,6- oxidopregnane-ZO-carboxylateTo a mixture of 331 grams of methyl 3,3-ethylenedioxy- A-pregnene-20-carb0xylate [K. Morita, Chem. Abs., 54, 4679 (1960)], gramsof potassium acetate, 166 grams of sodium sulfate, and 3300 millilitersof methylene chloride, there was added dropwise under ice cooling 275milliliters of 40 percent peracetic acid. The resulting reaction mixturewas stirred at 22 C. for 2 hours, treated with water and diluted withmethylene chloride. The methylene chloride phase was separated, washedwith sodium carbonate solution and water, dried over sodium sulfate andevaporated in vacuum to yield the desired 5,6-oxido-compound as anisomeric mixture.

(B) Synthesis of 5 3-H-compounds via 5,6-epoxides3- (1) Synthesis ofmethyl 213,35-dihydroxy-55,6;8-oxidopregnane-20-carboxylate The epoxidemixture as described in A above was dissolved in 2500 milliliters oftetrahydrofuran, treated at 0-5 C. with 690 milliliters of 3 Nperchloric acid and allowed to stand at 5 C. for 16 hours. The resultingsolution was stirred into 30 liters of ice water, neutralized and theprecipitated diol was filtered off by suction, washed and dried. Afterrecrystallization from acetone, there was obtained methyl5a,6fl-dihydroxypregnan-3one- 20-carboxylate, melting point 233-235 C.

To a solution of 10 grams of the 5a,6fl-diol in 128 milliliters oftetrahydrofuran there was added dropwise over 8 minutes with ice coolinga solution of 1.365 milliliters of bromine in 15 milliliters of glacialacetic acid. After stirring for an additional 5 minutes the reactionsolution was poured into ice water containing sodium acetate and thenextracted with methylene chloride. The methylene chloride solution waswashed until neutral, evaporated in 'vacuum at 30 C. and the residue wastriturated with isopropyl ether to yield methyl 2u-bromo-5a,6fidihydroxypregnan-3one-20-carboxylate.

To a mixture of 8.9 grams of the thus-obtained 2abromo-compound in 80milliliters of dry tetrahydrofuran, there was added at 0-5 C. a solution'of 9.6 grams of lithium tri(tert.-butoxy( aluminum hydride in 50milliliters of tetrahydrofuran. The resulting mixture was stirred into17 a sulfuric acid/ice water mixture, extracted with acetic ester,washed until neutral and evaporated in vacuum. Upon recrystallizationfrom isopropyl ether and then from acetone there was obtained methyl2a-bromo-35,5'a,65- trihydroxypregnane-Z-carboxylate, melting point 217-218 C. (dec.).

A solution of 8.5 grams of the thus-obtained triol in 85 milliliters ofglacial acetic acid was treated with 17 milliliters of acetic anhydrideand 850 milligrams of ptoluenesulfonic acid and then allowed to stand atroom temperature for 48 hours. The resulting solution was stirred intoice water and the resulting precipitate was filtered off by suction,washed with water and dried. After recrystallization from isopropylether, there was obtained methyl 2oz-bromo-35,5a,65-triacetoxypregnane20 carboxylate, melting point 211-213 C. (dec.).

A solution of 7.1 grams of the triacetate in 145 milliliters of glacialacetic acid was heated under reflux for 22 hours with 5 grams of silveracetate and 3 milliliters of water. The precipitate was filtered off bysuction and the filtrate was poured into ice water. The reaction productwhich precipitate was filtered off by suction, washed until neutral anddried. After chromatographing on silica :gel and recrystallization fromacetone/hexane, there was obtained methyl25,35,5a,65-tetraacetoxypregnane-Z0 carboxylate, melting point 202-203C.

A solution of 15.74 grams of the tetraacetate in 315 milliliters ofmethanol and 79 milliliters of water was refluxed for 2 hours with 11.8grams of potassium hydroxide and then neutralized with acetic acid.After vacuum distillation to remove the methanol, the residue wastreated with 200 milliliters of Water. The reaction product whichprecipitated w'as filtered off by suction, washed with water and dried.The crude carboxylic acid thus obtained was allowed to stand at roomtemperature for one hour in 200 milliliters of methylene chloride and200 milliliters of etheric diazomethane solution (manufactured from 30grams of nitrosomethylurea). After evaporation in vacuum, chromatographyof the residue on silica gel and recrystallization from acetone/hexane,there was obtained methyl 25,35 dihydroxy-S,65-oxidopregnane-20-carboxylate, melting point 185.5-186" C.

(2) Synthesis of methyl 25,35-isopropylidenedioxy-5,65-oxidopregnane-20-carboxylate A mixture of 300 milligrams of thetetraacetate produced as described above in 6 milliliters of a 10percent methanolic potassium hydroxide solution was allowed to stand atroom temperature for 16 hours. After acidification with 1 N hydrochloricacid, the solution was diluted with ethyl acetate, Washed until neutraland evaporated. The residue was admixed with 30 milliliters of ethericdiazomethane solution (manufactured from 2 grams of nitrosomethylurea)and allowed to stand for 2 hours. The resulting solution was evaporatedunder vacuum and the residue was purified by preparative thin layerchromatography to obtain methyl25,35,65-trihydroxy-5a-acetoxypregnane-ZO-carboxylate, melting point220-2215 C.

A mixture of 2.55 grams of the trihydroxy monoacetoxy compound, 0.4milliliter of boron trifiuoride etherate, and 100 milliliters of dryacetone was allowed to stand at room temperature for 30 minutes. Afterthe addition of 2 milliliters of pyridine, the reaction mixture wasevaporated under vacuum and the residue was precipitated with ice water.After filtering off the precipitate by suction, it was dried and thenrecrystallized from acetone/hexane to yield methyl25,35-isopropylidenedioxy-5u-acetoxy-65-hydroxypregnane-ZO-carboxylate,melting point 192.5-l93 C.

A mixture of 600 milligrams of this product, 48 milliliters of methanol,12 milliliters of water, and 1.8 grams of potassium hydroxide was heatedunder reflux for 3% hours. The mixture was then stirred into ice water,acidified with hydrochloric acid, and the resulting precipitate wasfiltered off by suction, Washed until neutral and dried. The crude acidwas dissolved in 5 milliliters of tetrahydrofuran and allowed to standfor 2 hours with 30 milliliters of etheric diazomethane solution. Theresulting solution was evaporated under vacuum and the residue wasfractionated by preparative thin layer chromatography to yield methyl25,35-isopropylidenedioxy-5,65-oxidopregnane-20- carboxylate, meltingpoint 149.5-150 C. and methyl 25, 35-isopropylidenedioxy 511,65dihydroxypregnane-20- carboxylate, melting point 266-267 C.

(3) Synthesis of methyl25,35-isopropylidenedioxy-5,6aoxidopregnane-ZO-carboxylate A mixture of200 milligrams of the 5a,65-diol produced as described above, 5milliliters of pyridine and 0.5 milliliter of methanesulfonic acidchloride was stirred at 5 C. for 16 hours. The resulting mixture waspoured into ice water, filtered by suction and dried. The crudeG-mesylate in admixture with 10 milliliters of pyridine, l0 millilitersof water, and 3 grams of sodium bicarbonate was heated under reflux for30 minutes. The resulting mixture was stirred into water and extractedwith methylene chloride. The methylene chloride solution was washed withdilute hydrochloric acid and water and then evaporated. Afterrecrystallization from acetone, there was obtained methyl25,35-isopropylidenedioxy 5,6a oxidopregnane-ZO-carboxylate, meltingpoint 199-201 C.

(4) Synthesis of methyl 25,35-dihydroxyand25,35-diacetoxy-55-pregnan-6-one-20-carboxylates (a) From methyl25,35-dihydroxy-S,65-oxidopregnane- 20-carboxylate.-A mixture ofmilligrams of methyl 25,35-dihydroxy-5,65-oxidopregnane 20 carboxylate,10 milliliters of benzene, and 0.1 milliliter of boron trifluorideetherate was stirred at room temperature for 20 hours. After theaddition of 0.5 milliliter of pyridine, the mixture was diluted withethyl acetate, washed in sequence with water, 1 N hydrochloric acid, andagain with water, dried and evaporated. From the residue there wasisolated by preparative thin layer chromatography methyl25,35-dihydroxy-55-pregnan-6-one-20-carboxylate, which afterrecrystallization from isopropyl ether/methylene chloride, melted at181.5-183" C.

(b) From methyl25,35-isopropylidenedioxy-5,65-oxidopregnane-ZO-carboxylate.-A mixtureof 100 milligrams of methyl 25,35-isopropylidenedioxy 5,65oxidopregnane-ZO-carboxylate, 5 milliliters of acetone and 0.2milliliter of boron trifluoride etherate was stirred at room temperaturefor 1 hour and then treated with 0.5 milliliter of pyridine andevaporated under vacuum. The residue was 'heated on a steam bath for 2hours in admixture with 10 milliliters of 61 percent acetic acid and 1drop of 2 N sulfuric acid. The resulting mixture was stirred into waterand extracted with chloroform. The extract was washed with water,evaporated and the residue was recrystallized from isopropyl ether toyield methyl 25,35-dihydroxy-55- pregnan-6-one-20-carboxylate identicalwith the compound produced inpart (a) above.

(c) Synthesis of methyl 25,35diacetoxy-55-pregnan-6-one-20-carboxylate.-A mixture of 200 milligrams of methyl 25,35dihydroxy-55-pregnan-6-one-20-carboxylate, 2-milliliters of .glacialacetic acid, 0.4 milliliter of acetic anhydride, and 20 milligrams ofp-toluenesulfonic acid was allowed to stand at 20 C. for 24 hours. Theresulting mixture was stirred into ice water and extracted withmethylene chloride. The methylene chloride solution was washed untilneutral, concentrated and recrystallized from isopropyl ether to yieldmethyl 25,35-diacetoxy-55-pregnan-6-one 20 carboxylate, melting point176.5l77.5 C.

(5) Synthesis of methyl 25,35-isopropylidenedioxy- SS-pregnan-6-one-20-carboxylate (a) From methyl25,35-isopropylidenedioxy-5,6a-oxidopregnane-20-carboxylate.A mixture of200 milligrams of methyl25,35-i'sopropylidenedioxy-5,6a-oxidopregnane-ZO-carboxylate, 10milliliters of benzene, and

0.2 milliliter of boron trifluoride etherate was stirred for hours atroom temperature. After workup as descibed in part (4)(a) above, therewas recovered methyl 25,35- isopropylidenedioxy 5Bpregnan-6-one-20-carboxylate, melting point 196.5-198 C. (from isopropylether).

(b) From methyl 25,3,B-dihydroxy-5 3-pregnan-6-one- 20-carboxylate.-Amixture of 150 milligrams of methyl 25,3fi-dihydroxy-SS-pregnan-6-one-2O-carboxylate, 10 milliliters of acetone, and 0.03milliliter of boron trifluoride etherate was allowed to stand at roomtemperature for 30 minutes. After workup as described above, there wasobtained methyl 2B,3fi-isopropylidenedioxy-SB-pregnan-6-one-20-carboxylate identical to that produced in part (a) above.

(C) Synthesis of 5fi-H-compounds via isomerization of 5a-H-compounds (1)Synthesis of methyl(S),2fi,3}3-diacetoxy-Soc-pregnan-6-one-20-carboxylate. An epoxidemixture produced in the manner described in A above was dissolved in2500 milliliters of tetrahydrofuran, treated with 690 milliliters of 3 Nperchloric acid and heated under reflux for 3.5 hours. The resultingsolution was stirred into liters of ice water, neutralized and theprecipitated dione filtered off by suction. After washing, drying, andrecrystallization from ethyl acetate, there was obtained methyl (20S),5apregnane 3,6 dione-20-carboxylate, melting point 212-214 C.

To a mixture of 37.45 grams of the 3,6-dione in 800 milliliters oftetrahydrofuran, there was added dropwise with ice cooling a solution of533 milliliters of bromine and 4.9 grams of potassium acetate in 50milliliters of glacial acetic acid. The resulting reaction solution waspoured into ice water containing sodium acetate. The precipitate whichformed was filtered off by suction and recrystallized from methanol toyield methyl (20$),2ubromo 5oz. pregnane-3,6-dione-20-carboxylate,melting point l61l62 C. (dec.).

A solution of 28 grams of the 2a-bromo-3,6-dione in 240 milliliters oftetrahydrofuran was diluted at 0-5 C. with a solution of 33.8 grams oflithium tri(tert.-butoxy) aluminum hydride in 160 milliliters oftetrahydrofuran. The resulting mixture was stirred into a sulfuricacid-ice water mixture and the precipitate which formed was filtered offby suction and recrystallized from ethyl acetate to yield methyl(20S),2a-bromo-3fl-hydroxy-5a-pregnan- 6-one-20-carboxylate, meltingpoint 211212 C.

A mixture of 19.4 grams of the resulting alcohol in 80 milliliters ofpyridine and milliliters of acetic anhydride was allowed to stand atroom temperature for 20 hours. The resulting mixture was stirred intoice water and the precipitate which formed was filtered off by suctionand recrystallized from acetone/hexane to yield methyl (20$),2a bromoSoc-pregnan-6-one-20-carboxylate, melting point 196-197 C.

A mixture of 81.2 grams of the product acetate, 800 milliliters ofglacial acetic acid, 16.2 milliliters of water and grams of silveracetate was heated under reflux for 20 hours. The precipitate whichformed was filtered off by suction and the filtrate was stirred into icewater. The resulting precipitate was filtered off by suction, washeduntil neutral, and dried. After recrystallization from methanol, therewas obtained 58.6 grams of methyl (20S),2/3,3fldiacetoxy-pregnan-6-one-20-carboxylate as a mixture of 502- andSB-isomers. After fractional crystallization from methylenechloride-isopropyl ether and methylene chloride-methanol, there wasrecovered the Sat-isomer, melting point 225-224" C., and the Sfi-isomer,melting point 176.5177.5 C.

(2) Synthesis of methyl 2p,3fl-diacetoxy-5a-A' -pregnan-6-one-20-carboxylate A mixture of 29.3 grams of the mixture of Soc-H-and 5 3-H-isomers produced as described above in 500 milliliters ofglacial acetic acid was treated dropwise with 3.3

grams of bromine in glacial acetic acid and the resulting mixture wasstirred at 50 C. for 2 hours. The reaction mixture was then stirred intoan ice/potassium acetate solution and the precipitate which formed wasfiltered off by suction, washed until neutral, and dried. Afterrecrystallization from acetone/hexane, there was obtained methyl (20S),28,313-diacetoxy-7a-bromO-Sa-pregnan-6-one-20-carboxylate, melting point152153 C.

'A mixture of 38 grams of the 7a-bromo compound, 10.3 grams of lithiumcarbonate, 6.2 grams of lithium bromide, and 380 milliliters ofdimethylformamide was heated at 120l25 C. for 4.5 hours under a nitrogenatmosphere. After filtration to remove undissolved lithium salts, thefiltrate was stirred into ice water. The precipitate which formed wasfiltered off by suction, dried and chromatographed on silica gel. Afterrecrystallization from isopropyl ether/methylene chloride, there wasobtained methyl (20S),2;8,3,8-diacetoxy 5a A pregnen-6-one-ZO-carboxylate, melting point 195-196 C.

(3) Synthesis of methyl 2/3,3 3-dihydroxyand 218,3/3- diaCetOxy-SB-A'-pregnen-6-one-20-carboxylate A solution of 500 milligrams of methyl25,3fl-diacetoxy-Sa-A' -pregnen-6-one-20-carboxylate, 20 milliliters ofethanol and 1.5 milliliters of 3 N hydrochloric acid was heated underreflux for 20 hours and worked up as described above. The resultingmixture of 5aand 55-H- isomers was then acetylated as described above toyield methyl (20S),2,8,3fi diacetoxy-5/i-A -pregnen-6-one-20-carboxylate, melting point 1945-1955 C. Hydrolysis of this product aspreviously described yields the corresponding methyl213,3B-dihydroxy-SB-H-isomer, melting point 224-226 C. (fromacetone/hexane).

(4) Synthesis of methyl 2fi,3B,l4a-trihydroxyand 25,3 3- diacetoxy 14o:hydroxy-Sfl-N-pregnen-6-one-20-carboxylate A mixture of 1.5 grams ofmethyl (20S),2/3,3p-diacetOXy-Sa-A' -pregnen-6-one-20-carboxylate, 1.5grams of selenium dioxide and 107 milliliters of dioxane was stirred atC. for 30 minutes. After filtering off the insoluble selenium, thefiltrate was stirred into ice water. The precipitate which formed wasfiltered off by suction, washed until neutral and dried. Afterrecrystallization from methanol, there was obtained methyl(20S),2p,3/3-diacetoxy- 14a-hydroxy-Su-N-pregnen-6-one-20-carboxylate,melting point 248-249.5 C.

A 300-milligram portion of the resulting product was heated under refluxin 10 milliliters of methanol and 0.5 gram of potassium hydroxide for 1hour and then worked up as described above. After recrystallization fromacetone, there was obtained methyl (20S),2fi,3fi,14t t-tl'lhydroxy-5,3-A-pregnen-6-one-20-carboxylate, melting point 238-240 C.

Employing procedures similar to those described above, 30 milligrams ofthe 2B,3fl,14u-trihydroxy compound were acetylated with l milliliter ofpyridine in 0.5 milliliter of acetic anhydride. After recrystallizationfrom acetone/hexane, there was obtained methyl (20S),2/3,3,8-diacetoxy-14a-hydroxy 5B A pregnen-6-one-20-carboxylate, melting point24 l-242 C.

(5) Synthesis of (22R),ZB,3B,14a,22,25-pentahydroxy- 5fi-A-cholesten-6-one (ecdyson) A mixture of 10 grams of methyl(2OS),2B,3/3-diacetoxy-5a-A -pregnen-6-one-20-carboxylate, 12 grams ofanhydrous lithium iodide, and milliliters of lutidine was heated underreflux for 2 hours. The resulting reaction mixture was poured into icewater, acidified with hydrochloric acid and saturated with sodiumchloride. The insoluble reaction product was filtered off by suction,dissolved in methylene chloride and chromatographed twice on silica gel.On recrystallization from acetone/hexane, there was obtained(20S),2/3,3,B-diacetoxy-Sfl-N-pregnen- 6-one-20-carboxylic acid, meltingpoint 245-247" C.

21 There was also recovered methyl (20R),25,35-diacetoxy- 55-A-pregnen-6-one-20-carboxylic acid, melting point 205.5-208 C. (fromacetone/hexane).

A mixture of 1.9 grams of the (20S),20-carboxylic acid, 38 millilitersof absolute tetrahydrofuran, and 10 grams of carbonyldiimidazole washeated for 20 minutes under reflux. The resulting reaction solution waspoured into ice water, acidified with hydrochloric acid, and saturatedwith sodium chloride. The insoluble imidazolide was separated and dried.A solution of a 2-gram portion of the imidazolide in 40 milliliters oftetrahydrofuran was treated with 2 grams of lithiumtri-(tert.-butoxy)aluminum hydride and then stirred at room temperaturefor 1 hour. The resulting mixture was then stirred into ice water,acidified with hydrochloric acid and, after bufi'ering with sodiumethylate, extracted with methylene chloride. After distillation of thesolvent, chromatographing on silica gel, and crystallization fromacetone/hexane, there was obtained (20S),25,35-diacetoxy-20-formyl-55- A-pregnen-6-one, melting point 200-202 C.

To an ethyl magnesium bromide solution (produced from 488 milligrams ofmagnesium and 1.68 milliliters of ethyl bromide in 25 milliliters ofether), there was added 3.86 milliliters of2-methyl-Z-tetrahydropyranyloxy- 3-butyne in 20 milliliters oftetrahydrofuran dropwise. After stirring for 30 minutes, the Grignardsolution was added to an ice-cooled solution of 820 milligrams of the20-forrnyl compound produced as described above in 20 milliliters oftetrahydrofuran and then stirred for 5 minutes. The reaction mixture wastreated with saturated ammonium chloride solution and the reactionproduct was taken up in ether, washed with saturated salt solution,dried and evaporated. After chromatographing on silica gel, there wasobtained (22R),25,35-diacetoxy-22- hydroxy 25 tetrahydropyranyloxy-S5-A-cholesten-23- yn-6-one, melting point 175-178 C. (from hexane/ ether).The (22S)-isomer (melting point 172-173 C.) was also obtained.

To a solution of 227 milligrams of this product in milliliters ofmethanol, there was added 60 milliliters of platinum dioxide and theresulting mixture was hydrogenated until hydrogen uptake ceased. Afterfiltration of the catalyst and evaporation of the solvent under vacuum,the residue was crystallized from actone/hexane to yield (22R),25,35,22trihydroxy 25 tetrahydropyranyloxy- 55-A' -cholesten-23-yn-6-one,melting point 147-150 C.

A solution of 100 milligrams of the thus-produced triol in 2 millilitersof dioxane was treated with 100 milligrams of selenium dioxide andheated for 1 hour at 90 C. The resulting reaction mixture was subjectedtopreparative thin layer chromatography and after crystallization fromtetrahydrofuran/pentane, there was obtained (22R), 2B,3/3,14oz,22,25pentahydroxy 55 A -cholesten-6-one (ecdyson), melting point 232-233 C.

Employing the (22S)-isomer isolated after the Grignard reaction, therewas produced in a similar manner (22S), 25,35,l4o,22,25 pentahydroxy 55A -cholesten-6-one (isoecdyson), melting point 227-230 C. (fromacetone).

EXAMPLE V From 3,3-ethylenedioxy-2O-hydroxymethyl-A -pregnen Employingprocedures similar to those described in Example IV-A,3,3-ethylenedioxy-20-hydroxymethyl-A pregnen was reacted with peraceticacid to produce the corresponding 5,6-epoxide, which was converted to20- hydroxymethyl-5a-pregnane-3,6-dione (melting point 180- 181 C.) bytreatment with perchloric acid in the manner described in Example IVC( 1Employing the techniques described in Example WC (1), the dione wasreacted with bromine to produce 2wbromo-20-hydroxymethyl-5a-pregnane-3,6-dione, the 2(1- bromo compoundwas reduced with lithium tri(tert.- butoxy)aluminium hydride to produce2u-bromo-35- hydroxy-20-hydroxymethyl-Su-pregnan-tS-one, followed byacetylation to 35-acetoxy-20-acetoxymethyl-2a-bromo-5apregnan-G-one(melting point 208-209 C.), and then reacted with silver acetate toproduce 25,35-diacetoxy-20- acetoxymethylpregnan-6-one as a mixture ofthe Sa-H- and 55-H-isomers.

Employing procedures similar to those described in Example IVC(2), theisomeric mixture was brominated to form25,35-diacetoxy-20-acetoxymethyl-7a-bromo-5apregnan-6-one (melting point147-l48 C.) which was dehydrobrominated to form25,35-diacetoxy-20-acetoxymethyl 5a A pregnen 6 one (melting point208.5- 209 C.)

The triacetate was reacted with selenium dioxide in the manner similarto that described in Example IVC(4) to produce 25,35diacetoxy-20-acetoxymethyl-l4a-hydroxy- 5a-A -pregnen-6-one, meltingpoint 253254 C.

A solution of 550 milligrams of 25,35-diacetoxy-20- acetoxymethyll4u-hydroxy 5a A pregnen 6 one in 27.5 milliliters of 1 percentpotassium hydroxide in methanol was heated at boiling for 30 minutes.The reaction mixture was then processed in a manner similar to theprocedure described in Example IC to obtain 25,35, 14oz trihydroxy 20hydroxymethyl-55-A' pregnen-6- one, melting point 255-257 C. (fromtetrahydrofuranethyl acetate).

A solution of 200 milligrams of 25,35,14a-trihydroxy-20-hydroxymethyl-55-A' -pregnen-6-one in 50 milliliters of acetone wastreated with 0.2 milliliter of boron trifiuoride etherate and processedas described in Example IID. There was obtained 25,35isopropylidenedioxy 140chydroxy-ZO-hydroxymethyl-55-A' -pregnen-6-one,melting point 240-241 C. (from acetone/hexane).

EXAMPLE VI From 3a-hydroxy-20,20-ethylenedioxypregnan-6-one3u-hydroxy-20,20-ethylenedioxypregnan-6-one was oxidized in known mannerto 20,20-ethylenedioxypregnane- 3,6-dione. Employing techniquesdescribed in Example IVC, the 3,6-dione was brominated to form 2a-bromo-20,20 ethylenedioxypregnane 3,6 dione, the 2u-bromocompound was reducedwith lithium tri(tert.-butoxy) aluminum hydride to formZea-bromo-35-hydroxy-20,20 ethylenedioxypregnan-G-one, the alcohol wasconverted to the corresponding 35 acetate, and the 2m bromo 35- acetoxy20,20 ethylenedioxy 5a pregnan-6-one was reacted with silver acetate toproduce 25,35-diacetoxy-20, 20-ethylenedioxypregnan-6-one as a mixtureof the SOC-H" and 55-H-isomers.

Employing procedures similar to those described in Example IVC, theisomeric mixture was brominated to form 25,35 diacetoxy 70cbromo-20,20-ethylenedioxy- Sa-pregnan-G-One, followed bydehydrobromination to 25, 35-diacetoxy-20,20-ethylenedioxy-5a-A'-pregnen-6-one.

Acidic ketal cleavage in known manner lead to 25,35- diacetOXy-Sa-A'-pregnene-6,20-dione. This dione was then reacted with2-methyl-2-tetrahydropyranyloxy-5-bromopentane, employing the knownWittig-reaction techniques, to produce25,35-diacetoxy-ZS-tetrahydropyranyloxy-Sa- A -cholestadiene-6-one.After selective epoxidation of the A -double bond, hydrolysis of theepoxide to the 20,22-diol and 14a-hydroxylation with selenium dioxide,there was obtained 25,35-diacetoxy-14a,20,22,25-tetrahydroxy-5ot-A'-cholesten-6-one.

A solution of 500 milligrams of 25,35-diacetoxy-14a,20,22,25-tetrahydroxy-A' -cholesten-6-one and 250 milligrams of potassiumcarbonate in milliliters of methanol was heated at boiling for 50minutes. The reaction mixture was then neutralized with acetic acid andevaporated to dryness in vacuo. Isolation and purification of thereaction product was accomplished by preparative layer chromatography onsilica gel using chloroform-methanol. There was obtained25,35,14a,20,22,25-hexahydroxy-55- A' -cholesten-d-one, melting point237.5-239.5 C.

What is claimed is:

1. The process for producing a compound of the for mula wherein R and Rare independently members selected from the group consisting of hydroxy,a radical derived from an aliphatic carboxylic acid of up to 11 carbonby removal of the carbon of the hydroxyl group and lower alkoxy;

R and R when taken together and R is in the ,8-

orientation are lower alkylenedioxy;

B represents the remainder of the steroid nucleus which comprisesheating the corresponding Sa-H-ketosteroid at elevated temperatures.

2. The process as in claim 1 wherein the compound produced is a compoundof the formula C CH:

R lwv wherein R and R are independently members selected from the groupconsisting of hydroxy, a radical derived from an aliphatic carboxylicacid of up to 11 carbons by removal of the carbon of the hydroxyl groupand lower alkoxy;

R and R when taken together and R is in the 13- orientation are loweralkylenedioxy;

A is a member selected from the group consisting of a single and adouble bond;

R when taken alone, is a member selected from the group consisting ofhydrogen and hydroxy;

R when taken alone, is a member selected from the group consisting of COZ, CHO, -CI-I--(O lower alkyl) aliphatic hydrocarbyl, and aliphatichydrocarbyl substituted with up to two substituents of the groupconsisting of hydroxy, a radical derived from an aliphatic carboxylicacid of up to 11 car bons by removal of the hydrogen of the carboxylgroup, lower alkoxy and tetrahydropyranyloxy;

R and R when taken together, are 0x0 or lower alkylenedioxy;

Z is a member selected from the group consisting of hydrogen and loweralkyl.

24 3. The process as in claim 2 wherein said elevated temperature is atleast 50 C.

4. The process as in claim 1 wherein the compound which is produced isof the formula CH3 R R7 CH3 I i on Rzlwv wherein R and R areindependently members selected from the group consisting of hydroxy, aradical derived from an aliphatic carboxylic acid of up to 11 carbons byremoval of the carbon of the hydroxyl group and lower alkoxy;

R and R when taken together and R is in the B- orientation are loweralkylenedioxy;

R when taken alone is a member selected from the group consisting ofhydrogen and hydroxy;

R when taken alone is a member selected from the group consisting of -COZ, --CHO,

aliphatic hydrocarbyl, and aliphatic hydrocarbyl substituted with up totwo substituents of the group consisting of hydroxy, a radical derivedfrom an aliphatic carboxylic acid of up to 11 carbons by removal of thehydrogen of the carboxyl group, lower alkoxy and tetrahydropyranyloxy;

R when taken alone and when R is hydrogen is a member selected from thegroup consisting of -CO Z, CHO, CH(O-lower alkyl) and aliphatichydrocarbyl and when R is hydroxy is R;

R and R when taken together are 0x0 or lower alkylenedioxy;

R and R when taken together are 0x0 or lower alkylenedioxy;

Z is a member selected from the group consisting of hydrogen and loweralkyl;

5. The process as in claim 4 wherein said elevated temperature is atleast 50 C.

References Cited UNITED STATES PATENTS 3,478,065 11/1969 Furst et al.260239.55 3,557,097 1/1971 Furst et a1. Z60-397.2

ELBERT L. ROBERTS, Primary Examiner US. Cl. X.R.

